Chemotherapy plays a key role in the treatment of a range of cancers including colo-rectal, breast and liver cancer. One drug frequently used in chemotherapy is 5-fluorouracil (5-FU) which is known to be a particularly potent anti-cancer agent. While 5-FU can be used independently in chemotherapeutic applications, typically the drug is used in combination with folinic acid as its calcium salt (leucovorin) (D. B. Longley, D. P. Harkin, and P. G. Johnston, “5-Fluorouracil: mechanisms of action and clinical strategies”, Nature Reviews: Cancer, Vol. 3, 330-338, 2003). The presence of folinic acid synergises the effect of 5-FU by specifically enhancing the capacity of 5-FU to inhibit thymidylate synthase.
In clinical use, the administration of 5-FU and folinic acid to a patient is performed in two separate injections and the optimal synergistic effect of the combination is not realised. Typically, an injectable solution of 5-FU is delivered intravenously at a pH of 9 which results in severe and painful vein damage (phlebitis) in the patient. Consequently a central line is typically used for delivery of 5-FU and this is a significant disadvantage of the present administration technique. Where 5-FU is formulated into a cream for topical use in the treatment of skin cancer, extensive inflammation and pain has been found to occur.
As such, there is a need for improvements in both the delivery of 5-FU and the combination anti-cancer therapy using 5-FU and folinic acid.
Compositions containing both 5-FU and folinic acid have been prepared at more physiologically acceptable pH levels. However these compositions have been shown to be unacceptable owing to the tendency of 5-FU to precipitate out of solution when a clinically appropriate concentration of 5-FU is used. Accordingly there is a need for a composition in which 5-FU and folinic acid can be co-administered at a physiologically acceptable pH at concentrations that are appropriate for clinical use.
The present inventors have surprisingly found that in the presence of a cyclodextrin derivative, a homogeneous solution of 5-FU and folinic acid can be prepared at a physiological pH which minimises harmful side effects.